Summary XR9051 (N-(4-(2-(6,7-Dimethoxy-1 .2,3,4,-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1 -methyl-2.5-dioxo-3-piperazinylidene) methylbenzamide) was identified as a potent modulator of P-gtycoprotein-mediated multidrug resistance (MDR) following a synthetic chemistry programme based on a natural product lead compound. The Correspondence to: P Chartton has been well documented. but at present its role in solid tumours is less clear.A broad range of compounds has been identified that are able to rexverse the MDR phenotype by interacting with P-gp and blocking the efflux of cvtotoxics from cells. These compounds include peptides. steroids. calcium channel blockers. cardiox ascular drugys and immunosuppressix e and antifungal agents (reviewed by Ford. 1996). Their use has been limited bx the inabilitN to achiexe clinically effectixe plasma or tumour concentrations to inhibit P-gp function before non-specific. deleterious toxicities are encountered (Lum et al. 1993: Raderer and Scheithaeur. 1993). The requirement for more selectixe and potent agents as resistance modifiers has led to the identification of a number of secondgeneration modulators. such as a non-immunosuppressix e cxclosporin derivatixe SDZ PSC 833 (Boesch et al. 1991). an acridonecarboxamide derixatixe. GG918 (Hvafil et al. 1993). and a triazinoaminopiperidine derixitixe. S9788 (Pierre et al. 19921. These compounds are currentlx in clinical trial. The demonstration that potent modulators can oxercome resistance in P-gp-oxerexpressing cell lines and tumours is a vital step in answerinc the question of whether inhibition of P-gp function w ill be an effectix e therapeutic strategy.XR9051 (Figure 1) xas identified from a medicinal chemistrx programme based on a diketopiperazine originally isolated from the fermentation of a Streptomyces species. In this paper. we descnrbe the in X itro profile of XR905 1. wxhich illustrates its promise as a nexx drug for the treatment of MDR tumours. 885

Overexpression of P-glycoprotein (P-gp) is a potential cause of multidrug resistance (MDR) in tumours. We have previously reported that XR9051 ( N -(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide) is a potent and specific inhibitor of P-gp, which reverses drug resistance in several murine and human MDR cell lines. In this study we have evaluated the in vivo efficacy of this novel modulator in a panel of murine and human tumour models and examined its pharmacokinetic profile. Efficacy studies in mice bearing MDR syngeneic tumours (P388/DX Johnson, MC26) or human tumour xenografts (A2780AD, CH1/DOXr, H69/LX) demonstrated that co-administration of XR9051 significantly potentiated the anti-tumour activity of a range of cytotoxic drugs. This modulatory activity was observed following parenteral and oral co-administration of XR9051. In addition, the combination schedules were well-tolerated. Following intravenous administration in mice, XR9051 is rapidly distributed and accumulates in tumours and other tissues. In addition, the compound is well-absorbed after oral administration. These data suggest that XR9051 has the potential for reversing clinical MDR mediated by P-glycoprotien. © 1999 Cancer Research Campaign